1. Field of the Invention
The present invention relates to the use of .beta..sub.3 -adrenergic agonists for the treatment of glaucoma and ocular hypertension by topical or systemic administration in mammals. More particularly, it relates to the use of ophthalmological compositions containing an active amount of these .beta..sub.3 -agonists or the pharmaceutical acceptable salts thereof for the treatment of glaucoma and ocular hypertension.
2. Description of the Prior Art
Glaucoma is an ocular disorder that causes functional or organic disturbances in the eyes due to continuous or repeated increase in intraocular pressure. Not only is there an increase in intraocular pressure, but also optic nerve cupping and visual field loss. Although the pathophysiological mechanism of open angle glaucoma is still unknown there is substantial evidence to suggest that the increased intraocular pressure is detrimental to the eye and that it is the most important factor causing degenerative damage in the retina. Primary open-angle glaucoma is an insidious, slowly progressive, bilateral condition. The condition is often asymmetric on presentation, however, so that one eye may have moderate or advanced damage and the fellow eye has minimal or no detectable damage. Most patients with primary open-angle glaucoma have elevated intraocular pressures in the range of 22 to 40 mm Hg. The cardinal features of open-angle glaucoma include elevated intraocular pressure, cupping and atrophy of the optic disc, and visual field loss. Individuals with intraocular pressures of 21 mm Hg or greater, normal visual fields, normal optic discs, open angles, and the absence of any ocular or systemic disorders contributing to the elevated intraocular pressures are referred to as having ocular hypertension. The concept of ocular hypertension is important because this set of findings occurs in 4% to 10% of the population over age 40. The term normal-tension glaucoma refers to typical glaucomatous optic disc cupping and visual field loss in eyes that have normal intraocular pressures, open angles, and the absence of any contributing ocular or systemic disorders. Normal tension glaucoma may be a consequence of the retina being unusually sensitive to pressure and therefore damage may occur at intraocular pressure levels otherwise considered physiologically normal. The clinical features of normal-tension glaucoma resemble primary open-angle glaucoma except for the absence of elevated intraocular pressure. Some authorities believe the visual field and optic disc changes are identical in normal-tension glaucoma and primary open-angle glaucoma, whereas others state subtle differences exist between the finding of the two conditions. If left untreated, glaucoma almost invariably leads to blindness. The course of the disease is typically slow with progressive loss of vision. Conventional therapy for glaucoma is based on lowering the intraocular pressure, either by drugs, laser therapy, or surgery. The treatment of glaucoma is required to reduce an intraocular pressure to the level adequate to maintain normal optic nerve functions.
Pilocarpine eye drops have been used extensively for the treatment of glaucoma. It is known however that pilocarpine eye drops not only reduce intraocular pressure but also act on the iris sphincter muscle and the ciliary muscle thereby causing side effects such as pupillary constriction, accommodative spasm as well as conjunctival congestion. Such side effects may invite very serious dangers particularly to persons operating motor vehicles. In the case of an elderly patient with cataracts, miosis will result in increased visual impairment.
Epinephrine eye drops are also associated with side effects such as conjunctival congestion, pain at the eyebrow and allergic blepharoconjunctivitis. The eye drops sometimes bring about increased intraocular pressure due to mydriasis.
Recently, .beta.-blockers have become promising in this field, and timolol maleate, levobunolol hydrochloride and betaxolol hydrochloride are commercially available. These drugs are .beta.-adrenergic antagonists that are believed to work by blocking the .beta.-adrenergic receptors in the ciliary epithelium and, thereby, decrease the production of aqueous humor, the clear fluid that circulates in the eye.
Drug therapy for glaucoma typically comprises topically instilled and/or orally administered medicines. Pilocarpine, epinephrine (and its prodrug form), and .beta.-blockers are frequently used as topical drugs and carbonic anhydrase inhibitors are used via systemic administration. Because of the incidence of significant side-effects associated with conventional medical therapy for glaucoma, there is a serious problem with patient compliance. The discomfort of taking these medicines results in patients not following their treatment schedules.
The problems associated with present commercially available drugs has encouraged development of new agents for the treatment of glaucoma. There is thus a need for the development of new agents which avoids the shortcomings and problems of the presently available medicaments.